反应详情

A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.027 g, 0.038 mmol), tert-butyl 4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate K, 0.260 g, 0.574 mmol), 5-bromo-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (Intermediate I, 0.150 g, 0.382 mmol), and potassium phosphate (0.325 g, 1.530 mmol) in 2.5 mL dioxane, 1 mL water was heated to 100° C. 2 hours. The reaction mixture was diluted with EtOAc and washed with 1 N citric acid solution. The organics were dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave tert-butyl 4-(2-(2-(N-(5-fluorothiazol-2-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.063 g, 0.099 mmol). This material was taken up in 1 mL THF, was treated with HCl 4N in dioxane (1.912 ml, 7.65 mmol) and was allowed to stir at room temperature overnight. The reaction mixture was concentrated yielding N-(5-fluorothiazol-2-yl)-5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride (0.063 g, 0.117 mmol). [M+H]+=538.8 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.82 (br. s., 2H), 7.73 (d, J=7.9 Hz, 1H), 7.60 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.30 (s, 1H), 7.25 (d, J=4.7 Hz, 2H), 7.02 (t, J=4.5 Hz, 1H), 5.71 (br. s., 1H), 4.29 (s, 2H), 3.62-3.68 (m, 1H), 3.53-3.59 (m, 2H), 3.37-3.44 (m, 1H), 3.18-3.28 (m, 2H), 2.85-3.07 (m, 2H), 2.06-2.20 (m, 1H), 1.92-2.02 (m, 1H)

1. custom2 hours
2. washwashed with 1 N citric acid solution
3. dry with materialThe organics were dried over MgSO4
4. concentrationconcentrated
5. customPurification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane)